Oncogenes are genes that can cause cancer. Carcinogenesis can occur by a wide variety of mechanisms, including infection of cells by viruses containing oncogenes, activation of protooncogenes in the host genome, and mutations of protooncogenes and tumor suppressor genes.
There are a number of viruses known to be involved in human cancer as well as in animal cancer. Of particular interest here are viruses that do not contain oncogenes themselves; these are slow-transforming retroviruses. They induce tumors by integrating into the host genome and affecting neighboring protooncogenes in a variety of ways, including promoter insertion, enhancer insertion, and/or truncation of a protooncogene or tumor suppressor gene. The analysis of sequences at or near the insertion sites led to the identification of a number of new protooncogenes.
With respect to lymphoma and leukemia, murine leukemia retrovirus (MuLV), such as SL3-3 or Akv, is a potent inducer of tumors when inoculated into susceptible newborn mice, or when carried in the germline. A number of sequences have been identified as relevant in the induction of lymphoma and leukemia by analyzing the insertion sites; see Sorensen et al., J. of Virology 74:2161 (2000); Hansen et al., Genome Res. 10(2):237-43 (2000); Sorensen et al., J. Virology 70:4063 (1996); Sorensen et al., J. Virology 67:7118 (1993); Joosten et al., Virology 268:308 (2000); and Li et al., Nature Genetics 23:348 (1999); all of which are expressly incorporated by reference herein.
In addition, breast cancer is one of the most significant diseases that affects women. At the current rate, American women have a 1 in 8 risk of developing breast cancer by age 95 (American Cancer Society, 1992). Treatment of breast cancer at later stages is often futile and disfiguring, making early detection a high priority in medical management of the disease.
KCNJ9 (Kir 3.3, GIRK3) is a member of the G-protein-activated inwardly rectifying potassium (GIRK) channel family. Vaughn J. et al., Biochem Biophys Res Commun (2000) Aug. 2; 274(2):302-9. In particular, the KCNJ9 gene encodes a G-protein-coupled inwardly rectifying potassium channel. Wolford J. K. et al., Mol Genet Metab (2001) May; 73(1):97-103.
The gene spans approximately 7.6 kb and contains one noncoding and two coding exons separated by approximately 2.2 and approximately 2.6 kb introns, respectively. Fourteen single nucleotide polymorphisms (SNPs), including one that predicts a Val366Ala substitution, and an 8 base-pair (bp) insertion/deletion have been identified, and earlier expression studies have revealed the presence of the transcript in various human tissues including pancreas, and two major insulin-responsive tissues: fat and skeletal muscle.
The comparative gene content and order are identical between mouse and human, indicating a high degree of conservation between the two species in the KCNJ9 region. Doudney K. et al., Genomics (2001) Mar. 1; 72(2):180-92. The genomic organization of the KCNJ9 locus on chromosome 1q21-23=makes it a candidate gene for Type II diabetes mellitus in the Pima Indian population. KCNJ9, however, has not before been associated with or implicated in cancer. All references cited herein are expressly incorporated in their entirety.
As demonstrated below, mutations that interrupt the KCNJ9 coding sequence result in cancer. Moreover, altered expression of KCNJ9 correlate with cancer, in particular with breast cancer.
Accordingly, it is an object of the invention to provide sequences involved in cancer and in particular in oncogenesis and breast cancer.